Phase I/II trial of lentiviral vector mediated gene therapy for Adenosine Deaminase deficiency

慢病毒载体介导的腺苷脱氨酶缺乏症基因治疗的 I/II 期试验

• 批准号: MR/K015427/1
• 负责人: Hubert Gaspar
• 金额: $ 156.27万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK015427%2F1
• 关键词: Phase; II; trial; lentiviral; vector

Adenosine deaminase deficiency(ADA) causes a severe problem with the development of the white cells in the blood and leads to a disease called severe combined immunodeficiency (SCID - also sometimes termed 'bubble babies'). Affected children are unable to fight infection and without treatment will die in the first year of life. The options for treatment are very limited. A bone marrow transplant is effective if a good donor can be found but in cases where an unrelated or mismatched donor has to be used, the procedure can be dangerous and 3-5 out of 10 children die from the effects of the transplant. Another treatment is regular injections of the ADA enzyme but this does not fully correct the white cells problems and children still remain vulnerable to infection.Gene therapy is way of introducing a working copy of the ADA gene into patients cells so that they can grow a new immune system. This has some advantages over a transplant because it uses the child's own cells. We and others have treated ADA patients in this way previously and 7 out of 10 children have been able to grow a new immune system. However, to carry the gene into the patient cells we and others used a disabled virus called a gammaretroviral vector (GRV). Unfortunately, in gene therapy treatments for other diseases, GRVs caused the development of leukaemia (a blood cancer) and trials had to be stopped. For these reasons, we want to develop a safer way of introducing the gene into patient cells. We are planning to use a different vector called a lentiviral vector (LV). We have tested LVs in the laboratory and shown that they are much safer than GRVs but also that they are equally good at correcting the immune system.We now want to see if they can treat patients effectively and safely. In this study, we plan to treat 10 patients with ADA SCID who do not have a good donor for transplant by gene therapy. We will introduce a working copy of the ADA gene into their bone marrow cells using a LV vector that has been prepared for use in patients. We will follow patients for 3 years to see if they can grow a new immune system and also to see if this treatment is safe. If we see a good response to the treatment in these 10 patients, then we hope that this will become a standard treatment for patients with ADA deficiency.

腺苷脱氨酶缺乏症 (ADA) 会导致血液中白细胞的发育出现严重问题，并导致一种称为严重联合免疫缺陷症（SCID - 有时也称为“泡泡婴儿”）的疾病。受影响的儿童无法抵抗感染，如果不接受治疗，他们将在出生后的第一年死亡。治疗的选择非常有限。如果能找到好的捐献者，骨髓移植是有效的，但如果必须使用不相关或不匹配的捐献者，则该过程可能很危险，十分之三的儿童会死于移植的影响。另一种治疗方法是定期注射 ADA 酶，但这并不能完全纠正白细胞问题，儿童仍然容易受到感染。基因疗法是将 ADA 基因的工作副本引入患者细胞中，以便他们能够生长出新的免疫系统。这比移植有一些优势，因为它使用孩子自己的细胞。我们和其他人之前曾以这种方式治疗 ADA 患者，十分之七的儿童能够长出新的免疫系统。然而，为了将该基因携带到患者细胞中，我们和其他人使用了一种称为伽马逆转录病毒载体（GRV）的失能病毒。不幸的是，在其他疾病的基因治疗中，GRV 导致白血病（一种血癌）的发展，试验不得不停止。出于这些原因，我们希望开发一种更安全的方法将该基因引入患者细胞。我们计划使用另一种称为慢病毒载体（LV）的载体。我们在实验室测试了 LV，结果表明它们比 GRV 安全得多，而且它们在纠正免疫系统方面同样出色。我们现在想看看它们是否能够有效、安全地治疗患者。在这项研究中，我们计划通过基因疗法治疗 10 名没有良好移植供体的 ADA SCID 患者。我们将使用已准备用于患者的 LV 载体将 ADA 基因的工作副本引入他们的骨髓细胞中。我们将跟踪患者三年，看看他们是否能够长出新的免疫系统，也看看这种治疗是否安全。如果我们在这 10 名患者中看到治疗反应良好，那么我们希望这将成为 ADA 缺陷患者的标准治疗方法。

项目成果

Gene Therapy Approaches to Immunodeficiency.

免疫缺陷的基因治疗方法。

• DOI: 10.1016/j.hoc.2017.05.003
• 发表时间: 2017
• 期刊: Hematology/oncology clinics of North America
• 作者: Ghosh S

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

• DOI: 10.1056/nejmoa2027675
• 发表时间: 2021-05-27
• 期刊: The New England journal of medicine
• 作者: Kohn DB;Booth C;Shaw KL;Xu-Bayford J;Garabedian E;Trevisan V;Carbonaro-Sarracino DA;Soni K;Terrazas D;Snell K;Ikeda A;Leon-Rico D;Moore TB;Buckland KF;Shah AJ;Gilmour KC;De Oliveira S;Rivat C;Crooks GM;Izotova N;Tse J;Adams S;Shupien S;Ricketts H;Davila A;Uzowuru C;Icreverzi A;Barman P;Campo Fernandez B;Hollis RP;Coronel M;Yu A;Chun KM;Casas CE;Zhang R;Arduini S;Lynn F;Kudari M;Spezzi A;Zahn M;Heimke R;Labik I;Parrott R;Buckley RH;Reeves L;Cornetta K;Sokolic R;Hershfield M;Schmidt M;Candotti F;Malech HL;Thrasher AJ;Gaspar HB
• 通讯作者: Gaspar HB

Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency.

• DOI: 10.1016/j.jaci.2018.08.024
• 发表时间: 2019-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Kohn DB;Hershfield MS;Puck JM;Aiuti A;Blincoe A;Gaspar HB;Notarangelo LD;Grunebaum E
• 通讯作者: Grunebaum E

Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency.

• DOI: 10.3389/fimmu.2016.00314
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Whitmore KV;Gaspar HB
• 通讯作者: Gaspar HB